Cardiac optogenetics: the next frontier

Abstract

The emerging technology of optogenetics uses optical and genetic means to monitor and modulate the electrophysiological properties of excitable tissues. While transforming the field of neuroscience, the technology has recently gained popularity also in the cardiac arena. Here, we describe the basic principles of optogenetics, the available and evolving optogenetic tools, and the unique potential of this technology for basic and translational cardiac electrophysiology. Specifically, we discuss the ability to control (augment or suppress) the cardiac tissue's excitable properties using optogenetic actuators (microbial opsins), which are light-gated ion channels and pumps that can cause light-triggered membrane depolarization or hyperpolarization. We then focus on the potential clinical implications of this technology for the treatment of cardiac arrhythmias by describing recent efforts for developing optogenetic-based cardiac pacing, resynchronization, and defibrillation experimental strategies. Finally, the significant obstacles and challenges that need to be overcome before any future clinical translation can be expected are discussed.

Optogenetics: Background, Methodological Advances and Potential Applications for Cardiovascular Research and Medicine

“…Such methods may employ direct delivery of genes (with or without vehicles) and utilize physical cues, such as electric field (electroporation), ultrasound waves (sonoporation), laser pulse (photoporation), hydrodynamic pressure (hydroporation) etc., to enhance gene delivery (Ramamoorth and Narvekar, 2015). Newer methods are also investigating indirect photosensitization method via transplantation of photosensitive cells in the target regions (Gruber et al, 2018). A gene delivery method is ideal for cardiac optogenetics if it is robust, efficient, stable, scalable, and also provides sufficient packaging capacity but elicits minimal offtarget, inflammation, disease, toxicity, and mutagenesis (Wasala et al, 2011;Lentz et al, 2012).…”

“…Despite these advances, cardiac optogenetics is still in a nascent stage for clinical translation (Gruber et al, 2018). One key approach to move closer to human application would be in scaling up the system to larger animal models, such as pig, which would better mimic human heart anatomy (Boyle et al, 2018).…”

“…Next, emphasis should also be given to the in silico approaches that provide appealing tools in modeling different systems, such as heterogeneity in opsin expression, light absorption, illumination pattern, and in scaling up the system to meet clinically relevant sizes and also in predicting the outcomes accordingly (Boyle et al, 2013;Karathanos et al, 2016). On the other hand, since most of the present day observations are obtained from unconscious and immobilized animal models, another strategy to advance toward translational medicine would be to develop technologies feasible on freely moving and conscious experimental animals; such models would best mimic the native physiological states (Gruber et al, 2018). Furthermore, integration of recent developments on biocompatible integumentary membrane and micro LED array can expedite development of optogenetic membrane that can contract along the myocardial surface and provide optical stimulation at multiple locations simultaneously; such technology is particularly appealing for optogenetic defibrillation method that requires stimulation of a larger myocardial area (Boyle et al, 2015).…”

“…One of the key considerations for clinical application of cardiac optogenetics is on the safe, stable, and uniform opsin expression in human heart (Pianca et al, 2017). Concerns of toxicity and immunogenicity may arise with opsin expression in cardiac applications that requires high opsin levels for robust photocurrents (Boyle et al, 2015;Gruber et al, 2018). Besides, safe and appropriate vehicle types and administration routes must be well-established for intended applications .…”

“…In this regard, although many novel technologies are emerging to address such needs, they are yet to be validated in appropriate animal models. For instance, tandem cell unit has only been validated in in vitro settings because of possible issues of cell engraftment and host-graft coupling for in vivo applications (Pianca et al, 2017;Gruber et al, 2018). Next, possible concerns of nonuniform opsin expression (which may render heterogeneous cell depolarization and induce substrate for arrhythmias), ectopic opsin expression and immune concerns with hostspecific antibodies to viral vectors, etc.…”